Coronary artery disease (CAD) is the leading cause of mortality in the developed world, and is associated with substantial morbidity as well. Typically, the patient with CAD has several concomitant conditions, including hypertension, diabetes, and dyslipidemia, increasing overall risk for poor outcomes and complicating treatment.
Among antihypertensive therapies, the lipophilic dihydropyridine-type calcium channel blocker CCB) amlodipine besylate (AML) is a very well-tolerated agent with an established record of safety and effectiveness for the treatment of hypertension and angina. A potential therapeutic role for AML in the treatment of patients with CAD was recently shown in the Prospective Randomized Evaluation of the Vascular Effects of Norvasc® (AML) Trial (PREVENT). This three-year trial evaluated the effects of AML compared to placebo on the development and progression of atherosclerotic lesions in coronary and carotid arteries among patients with documented CAD (Byington R P, Miller M E, Herrington D, et al. Rationale, design, and baseline characteristics of the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT). Am. J. Cardiol. 1997; 80:1087–1090). The results of PREVENT showed impressive clinical benefits with AML therapy, including an overall 30% reduction in major documented events or procedures (Byington R P, Chen J, Furberg C D, Pitt B. Effect of amlodipine on cardiovascular events and procedures. J. Am. Coll. Cardiol. 1999; 33:314A and Pitt B, Byington R P, Hunninghake D B, Mancini J, Miller M E, Riley W. Effect of amlodipine on the progression of atherosclerosis and occurrence of clinical events. Circulation 2000; 102:1503–1510). AML therapy was also associated with a significant slowing in the progression of carotid atherosclerosis, as measured by B-mode ultrasonographic assessments (Byingyton R, Riley W, Booth D, et al. Effect of amlodipine on progression of carotid atherosclerosis in patients with documented heart disease. Am. J Hypertens. 1999; 12:42A–43A and Pitt B, Byington R P, Hunninghake D B, Mancini J, Miller M E, Riley W. Effect of amlodipine on the progression of atherosclerosis and occurrence of clinical events. Circulation 2000; 102:1503–1510). The clinical benefit seen with AML in CAD has not been previously reported with other CCBs, including dihydropyridine-type agents that have been used to examine this question (Waters D, Lesperance J, Francetich M, et al. A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis. Circulation 1990; 82:1940–1953; Lichtlen P R, Hugenholtz P G, Rafflenbeul W, et al. Retardation of coronary artery disease in humans by the calcium-channel blocker nifedipine: Results of the INTACT study (International Nifedipine Trial on Antiatherosclerotic Therapy). Cardiovasc. Drugs Ther. 1990; 4:S1047–S1068; Borhani N O, Mercuri M. Borhani P A, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA 1996; 276:785–791). This observation has led to interest in potential antiatherogenic properties of AML, including antioxidant effects that are independent of calcium channel modulation (Mason R P, Leeds P R, Jacob R E, et al. Inhibition of excessive neuronal apoptosis by the calcium antagonist amlodipine and antioxidants in cerebellar granule cells. J. Neurochem. 1999; 72:-1448–1456; Tulenko T N, Laury-Kleintop L, Walter M F, Mason R P. Cholesterol, calcium and atherosclerosis: Is there a role for calcium channel blockers in atheroprotection? Int. J. Cardiol. 1997; 62 (2 Suppl):55S–66S; Kramsch D M, Sharma R C. Limits of lipid-lowering therapy: The benefits of amlodipine as an anti-atherosclerotic agent. J Hum. Hypertens. 1995; 9 (Suppl 1:S3–S9); and Mason R P, Walter M F, Trumbore M W, Olmstead E G, Mason P E. Membrane antioxidant effects of the charged dihydropyridine calcium antagonist amlodipine. J. Mol. Cell. Cardiol 1999; 1:275–281.
Hypolipidemic therapy has also been demonstrated to be very useful in reducing morbidity and mortality associated with CAD. The ortho- and para-hydroxylated metabolites of atorvastatin ATM have been shown to exhibit antioxidant effects in lipoprotein preparations (Aviram M, Rosenblat M, Bisgaier C L, Newton R S. Atorvastatin and gemfibrozil metabolites but not the parent drugs, are potent antioxidants against lipoprotein oxidation. Atherosclerosis 1998: 138:271–280). The ortho-, meta-, and para-hydroxylated metabolites of atorvastatin (ATM) and their methods of preparation are shown in U.S. Pat. No. 5,385,929.
However, no pharmaceutical composition currently exists that treats both hypertension and hyperlipidemia. Such a pharmaceutical composition would have several benefits. For example, the multiple risk factors for arterial and related heart disease that are often present in an individual patient could be targeted simultaneously. Additionally, the ease of taking one combined dosage could significantly enhance patient compliance with therapeutic regimens.
Therefore, it is an object of this invention to provide a combination therapy that will treat the multiple pathological processes involved in arterial and related heart disease.
These include, but are not limited to, hypertension and hyperlipidemia. It is also an object of is invention to develop useful and convenient dosage levels and forms of such a combination therapeutic. Preferably, this pharmaceutical composition would have synergistic effects on these hallmarks of arterial and related heart disease, such that the individual effects of the components of this composition would be enhanced by their combination.
Thus, this invention encompasses a therapeutic goal for the treatment of CAD that entails the development of drugs that can simultaneously target multiple underlying disease processes that contribute to atherosclerosis, thereby altering the course of the disease. Therefore, using this invention, CAD therapy may have increased positive outcomes if the use of an antihypertensive agent and HMG-CoA reductase inhibitor was combined in a single delivery system.